Journal
BLOOD ADVANCES
Volume 4, Issue 20, Pages 5165-5173Publisher
ELSEVIER
DOI: 10.1182/bloodadvances.2019001307
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Funding
- Program for an Integrated Database of Clinical and Genomic Information [17kk0205005h0002, 18kk0205005s0203]
- Program for a CancerResearch and Therapeutic Evolution from the Japan Agency for Medical Research and Development [18cm0106501h0003JP]
- Japan Society for the Promotion of Science [17K10136]
- Takeda Science Foundation
- Ministry of Health, Labour and Welfare of Japan [H14-Koka(Gan)-031, H15-Koka(Gan)024, H16-GanRinsho-004, H17-GanRinsho-004, H20-GanRinshoIppan-017, H23-GanRinsho-Ippan-014]
- RIKEN Advanced Institute for Computational Science through the HPCI System Research project [hp150232]
- [16ck0106066h0003]
- [17ck0106253h0001]
- [18ck0106253h0002]
- Grants-in-Aid for Scientific Research [17K10136] Funding Source: KAKEN
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Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n = 116) and/or array-based gene expression analysis (n = 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n = 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.
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